This project focuses on basic and applied research on human retroviruses, HIV-1 and HTLV-I. It covers three broad areas: I) basic research studying the regulated expression of HIV-1; II) basic research on cellular transformation events as related to HTLV-I; and III) applied research towards developing small molecular inhibitors targeted against HIV-1. Some notable scientific advances from our research program in 2004-2005 include: 1) the finding that human RNA helicase DDX3 is a critical cofactor for HIV-1 post-transcriptional gene expression; 2) the characterization of polyarginine as an inexpensive inhibitor of HIV-1 envelope processing; 3) the proposal that HIV-1 encode microRNAs; 4) the demonstration of a rare siRNA sequence in HIV-1, 5) the characterization of pathways used by Tax to repress p53, and 6) the study of the Ku protein as a target of the HTLV-1 oncoprotein.